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Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and -independent pathways

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Abstract

Excess glucocorticoid administration impairs osteogenic activities, which raises the risk of osteoporotic disorders. Epigenetic methylation of DNA and histone regulates the lineage commitment of progenitor cells. This study was undertaken to delineate the actions of histone lysine demethylase 6a (UTX) with regard to the glucocorticoid impediment of osteogenic differentiation. Osteogenic progenitor cells responded to supraphysiological glucocorticoid by elevating CpG dinucleotide methylation proximal to transcription start sites within Runx2 and osterix promoters and Wnt inhibitor Dickkopf-1 (Dkk1) expression concomitant with low UTX expression. 5′-Aza-deoxycystidine demethylation of Runx2 and osterix promoters abolished the glucocorticoid inhibition of mineralized matrix accumulation. Gain of UTX function attenuated the glucocorticoid-induced loss of osteogenic differentiation, whereas UTX silencing escalated adipogenic gene expression and adipocyte formation. UTX sustained osteogenic gene transcription through maintaining its occupancy to Runx2 and osterix promoters. It also mitigated the trimethylation of histone 3 at lysine 27 (H3K27me3), which reduced H3K27me3 enrichment to Dkk1 promoter and thereby lowered Dkk1 transcription. Modulation of β-catenin and Dkk1 actions restored UTX signaling in glucocorticoid-stressed cells. In vivo, UTX inhibition by exogenous methylprednisolone and GSK-J4 administration, an effect that disturbed H3K27me3, β-catenin, Dkk1, Runx2, and osterix levels, exacerbated trabecular microarchitecture loss and marrow adiposity. Taken together, glucocorticoid reduction of UTX function hindered osteogenic differentiation. Epigenetic hypomethylation of osteogenic transcription factor promoters and H3K27 contributed to the UXT alleviation of Dkk1 transcription and osteogenesis in glucocorticoid-stressed osteogenic progenitor cells. Control of UTX action has an epigenetic perspective of curtailing glucocorticoid impairment of osteogenic differentiation and bone mass.

Key messages

  • UTX attenuates glucocorticoid deregulation of osteogenesis and adipogenesis.

  • UTX reduces Runx2 promoter methylation and H3K27me3 enrichment in the Dkk1 promoter.

  • β-catenin and Dkk1 modulate the glucocorticoid inhibition of UTX signaling.

  • UTX inhibition exacerbates bone mass, trabecular microstructure and fatty marrow.

  • UTX signaling is indispensable in fending off glucocorticoid-impaired osteogenesis.

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Acknowledgements

This work was supported in part by grants NHRI-EX105-10436SI from the National Health Research Institute; MOST103-2314-B-182A-053 from the Ministry of Science & Technology; and CLRPG8B0042, CMRPG8B0873, CMRPG8E1321-3, and CMRPG8E0651-3 from Chang Gung Memorial Hospital, Taiwan.

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    Authors and Affiliations

    1. Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan

      Feng-Sheng Wang, Wei-Shiung Lian, Wen-Tsan Weng, Yu-Shan Chen, Yi-Chih Sun, Shing-Long Wu & Pei-Chin Chuang

    2. Core Laboratory for Phenomics and Diagonistics, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan

      Feng-Sheng Wang, Wei-Shiung Lian, Wen-Tsan Weng, Yu-Shan Chen, Yi-Chih Sun & Shing-Long Wu

    3. Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan

      Feng-Sheng Wang & Jih-Yang Ko

    4. Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan

      Mel S. Lee & Jih-Yang Ko

    5. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung, 83303, Taiwan

      Ying-Hsien Huang

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    1. Feng-Sheng Wang
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    Correspondence to Pei-Chin Chuang or Jih-Yang Ko.

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    Research grant support

    Grants NHRI-EX105-10436SI from the National Health Research Institute; MOST103-2314-B-182A-053 from the Ministry of Science & Technology; and CLRPG8B0042, CMRPG8B0873, CMRPG8E1321-3, and CMRPG8E651-3 from Chang Gung Memorial Hospital, Taiwan

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    F.-S.W., W.-S.L., and M.S. Lee equally contributed to this study.

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    Wang, FS., Lian, WS., Lee, M.S. et al. Histone demethylase UTX counteracts glucocorticoid deregulation of osteogenesis by modulating histone-dependent and -independent pathways. J Mol Med 95, 499–512 (2017). https://doi.org/10.1007/s00109-017-1512-x

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